Abstract
ARF is a multifunctional tumor suppressor that acts as both a sensor of oncogenic stimuli and as a key regulator of ribosome biogenesis. Recently, our group established the DEAD-box RNA helicase and microRNA (miRNA) microprocessor accessory subunit, DDX5, as a critical target of basal ARF function. To identify other molecular targets of ARF, we focused on known interacting proteins of DDX5 in the microprocessor complex. Drosha, the catalytic core of the microprocessor complex, has a critical role in the maturation of specific non-coding RNAs, including miRNAs and ribosomal RNAs (rRNAs). Here, we report that chronic or acute loss of Arf enhanced Drosha protein expression. This induction did not involve Drosha mRNA transcription or protein stability but rather relied on the increased translation of existing Drosha mRNAs. Enhanced Drosha expression did not alter global miRNA production but rather modified expression of a subset of miRNAs in the absence of Arf. Elevated Drosha protein levels were required to maintain the increased rRNA synthesis and cellular proliferation observed in the absence of Arf. Arf-deficient cells transformed by oncogenic RasV12 were dependent on increased Drosha expression as Drosha knockdown was sufficient to inhibit Ras-dependent cellular transformation. Thus, we propose that ARF regulates Drosha mRNA translation to prevent aberrant cell proliferation and Ras-dependent transformation.
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Acknowledgements
We thank the members of the Weber lab for their technical input and suggestions. The Children’s Discovery Institute and the Genome Institute at Washington University provided lentiviral knockdown constructs. MJK was supported by the Siteman Cancer Center, Cancer Biology Pathway Training Grant (T32 CA113275). Grants from the National Institutes of Health (R01 CA120436) and Department of Defense Era of Hope Scholar Award (BC075004) to JDW supported this work.
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Kuchenreuther, M., Weber, J. The ARF tumor-suppressor controls Drosha translation to prevent Ras-driven transformation. Oncogene 33, 300–307 (2014). https://doi.org/10.1038/onc.2012.601
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DOI: https://doi.org/10.1038/onc.2012.601
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